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Advances In The Synthesis Of Glycerides Of Fatty AcidsL. Hartman
Chem. Rev., 1958, 58 (5), 845-867• DOI: 10.1021/cr50023a002 • Publication Date (Web): 01 May 2002
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ADVANCES I N THE SYXTHESIS OF GLYCERIDES O F FATTY ACIDS
L . HARTMAN
Fa t s Res ea r ch La b o r a t o r y , Dep a r t men t of S c i en t i f i c a n d In d u s t r i a l Res ea r ch ,
W e l l i n g t o n , N e w Z e a l a nd
R ec e iv ed J a n u a r y SO , 1958
CONTENTS
I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84511. General considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846
111. Preparation of chlorides of fatty acids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847IV. Synthesis of monoglycerides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
B. j3-Monoglycerides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 850
A . a-Monoglycerides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
A . a,&'-Diglycerides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .V . Synthesis of diglycerides.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
B. a,p-Diglycerides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 854
A . Simple triglycerides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856B. Diacid triglycerides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . , , , . , , , . . , , , , , , , , 857C. Triacid triglycerides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
VII. Criteria of purit'p and stru ctu re. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861A . Oxidation JTith perio dat es. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861B. Chromatographic methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861
862D. Infrared spectra. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862E. Conclusive proof of s t ruc tu re . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
VIII. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
VI. Synthesis of triglycerides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
C . Thermal and x-ray investigation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
I. INTRODUCTIOT
The chemistry of synthetic glycerides of fatt y acids was reviewed by Dauberta i d King (40) in 1911. The present review describes recent progress in this field
and covers the period from 1940 to December, 1957. Its purpose is to outlinemethods of glyceride synthesis developed during this period, to supply the char-
acteristics of the synthesized products, and to outline some recent techniquesuyed in the estimation and definition of glycerides. The discussion mill be limited
to glycerides of fatty acids with the exclusion of the related phospholipides. The
synthesis of optically active glycerides, however, will be reviewed, since these
glycerides seem to form an integral part of fats.Accounts of synthetic glycerides may be found in textbooks such as that of
Hilditch (73) or Ralston (126) and from time to time in the section on lipides of
the Annual Reviews of Biochemistry, but no review as comprehensive as that of
Daubert and King (40), previously mentioned, seems to have appeared in recent
years. The excellent survey by Verkade (144) of the synthesis of glycerides
deals essentially with the work carried out in his laboratory.After the manuscript of this article had been completed an article by ,\ Idkin
sild Bevan (102) on the synthesis of glycerides appeared.
1 Tri tJ l = triphenylmethyl.
845
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846 L. HARTMAN
11. GENER.4L CONSIDERATIONS
The nomenclature of glycerides, which lacks consistency, requires a brief
reference. There is no agreement as to the designation of the carbon atoms of
glycerol, both Greek letters and numbers being used. In conformity with theprevious review in this Journal the symbols a , p, and a’ have been retained. T o
avoid confusion the various crystalline forms of glycerides, which are a t present
the subject of much controversy, will be denoted with Roman numerals. The
terms “simple” diglycerides and triglycerides and the slightly ambiguous terms“diacid” diglycerides (diglycerides with two different acyl groups) and “diacid”
and “triacid” triglycerides (triglycerides with two similar and three different
acyl groups, respectively) mill be used throughout the text for the sake of brevity.
Strictly speaking, even the terms monoglyceride, diglyceride, and triglyceride
are misnomers; nevertheless they are generally accepted in the chemical nomen-
clature.
The danger of acyl migration and intermolecular exchange of f at ty acids inthe course of synthesis is now generally recognized, and this knowledge has
eliminated the source of many previous errors. On the other hand, the purification
of starting materials is not always effected with sufficient care, and results of
some interesting recent investigations have been impaired because of the in-sufficient purity of the fat ty acids used. Despite the extensive literature on the
subject the synthesis of glycerides is still an a rt which comparatively few lab-
oratories have fully mastered. With the partial exception of a-monoglycerides
there are still no truly reliable methods of determining the purity of intermediate
and final products, although some chromatographic and infrared procedures
are promising in this respect. Determinations of saponification equivalents,iodine numbers, and of carbon and hydrogen content have only a limited value,and melting points are by no means conclusive. Thus melting points differing
by as much as 5-6°C. have been reported recently for some glycerides (cr-stearyl-a’-olein, CY , -dimyristin, a-oleyldistearin, and a-palmityldielaidin) by reputable
investigators.Despite these limitations, and although no radical changes in the methods of
glyceride preparation have occurred during the period under review, a measureof progress has been achieved. This progress can be summarized as follows:
1. The range of pure synthetic glycerides has been extended to cover those
containing one or more unsaturated acids.
2 , Compounds unobtainable by previous methods, such as the p-mono-glycerides of unsaturated acids, have been prepared for the first time.
3 . The synthesis of pure glycerides has been effected without recourse to
blocking by means of “directed interesterification” or by utilizing the
different reactivity of the primary and secondary hydroxyl groups of
glycerol.
3 . Several new glycerides containing short-chain fatty acids such as acetic
acid have been prepared, and their properties have been studied with
the view to practical application.
The last two developments inight be described as a “back to Berthelot move-
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S YNT HE S I S OF GL YC E R I DE S O F FATTY ACIDS 847
ment,” inasmuch as the originator of the chemistry of synthetic glycerides
employed exclusively direct esterification methods (17) and stressed the fertility
of glyceride synthesis as extending beyond t’he mere reproduction of natural
fats (18).
111. PREPARATIOX O F CHLORIDES O F FATTY ACIDS
Pure glycerides are prepared as a ule from chlorides of fatty acids. As a result
of a systematic investigation of various chlorinating agents Bauer (11)concluded
that phosphorus tri- and pentachlorides are superior to other reagents for the
preparation of chlorides of saturated fatt y acids, but that chlorides of unsatu-
rated fatty acids are best prepared by using oxalyl chloride. The same author
developed also a convenient method of estimating unreacted fat ty acids, basedon the conversion of fa tty acid chlorides into anilides. Bauer’s results with oxalyl
chloride are in agreement with the findings of other investigators (152), according
to which oleyl, elaidyl, linoleyl, and linolenyl chlorides can be successfully pre-pared with this reagent with a minimum rearrangement of double bonds. Oxalyl
chloride has been also used with great success for the preparation of chlorides
of saturated fatty acids, but its high price has led various investigators to use
the much cheaper thionyl chloride, which was found quite satisfactory for this
purpose. The use of thionyl chloride for the preparation of chlorides of unaatu-rated acids offers difficulties owing to the formation of tarry products. According
to Verkade (143) this can be avoided by purifying thionyl chloride by distillation
over quinoline and linseed oil. Still more effective is the use of theoretical amounts
of thionyl chloride in the presence of an equimolar quantity of pyridine in an
organic solvent ( 7 5 ) ,which reduces considerably the time and temperature ofthe reaction.Crude chlorides of fa tty acids are usually purified by distillation in vucuo. By
an improved distillation technique (31) the yields of 56-89 per cent reported
by Bauer (11) for some preparations could be improved to 89-98 per cent.
Further improvements, including dispensing with the distillation of the crude
acid chlorides, have been suggested very recently (153). The fatty acids aredissolved in 10 volumes of solvent (benzene, Skellysolve F, or carbon tetra-
chloride) and refluxed with an excess of phosphorus tr i- or pentachloride. The
excess of the chlorinating agent is removed by washing with water. Quantitative
recoveries of acid chlorides with only 1-2 per cent of free acid (estimated by a
rapid infrared technique) are claimed. Phosphorus pentachloride is more efficientthan the trichloride.
The use of phosgene as chlorinating agent in the presence of a tertiary amine
as catalyst (138) or without a catalyst (124) does not seem to hold great promiseas a laboratory method.
IV. S YS T H E S I S OF M OXOGL YCE R IDE S
A . a-Monoglycerides
The classical monoglyceride synthesis from isopropylideneglycerol (acetone-
glycerol) (60) still remains the most reliable method, although recently some
doubts have been raised as to the purity of the products thus obtained (125).
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848 L. HARTMAN
Since a-monoglycerides form the basis of the glyceride synthesis, there havebeen several suggestions in the past aiming at the simplification of the original
acetoneglycerol procedure. Recently it has been suggested (118) that acetone
be condensed with glycerol in the presence of p-toluenesulfonic acid, removing
the water formed by azeotropic distillation iyith light petroleum. It has been
also suggested that the fatty acid be introduced by interesterification n-ith a
fa t ty acid methyl ester in the presence of lead oxide instead of the usual acylationwith an acid chloride. This modification might have some merit. On the other
hand, the proposal to use glycerol formal (obtained by the condensation of
formaldehyde with glycerol) instead of acetoneglycerol is apparently impractical
because of the difficulty of hydrolyzing this compound after acylation (83).
N o other blocking technique for preparing a-monoglycerides has acquired an
importance comparable with that of the acetoneglycerol method. Ditrityl-glycerol’ according to Verkade (144), a recognized authority on trityl compounds,
is inferior as start ing material to acetoneglycerol. The oxidation of allyl esterswith potassium permanganate to form monoglycerides has been revived (142),
but the purity of the products m s only about 90 per cent owing to side reactions.
The interesterification of fats with glycerol has been shown ( 5 2 ) to proceed
substantially according to chance, producing a random mixture of mono-, di-,and triglycerides. A similar study was carried out recently of the mechanism
of the reaction between fat ty acids and glycerol (l oa ). Many suggestions have
been made to increase the proportions of monoglycerides in the final mixture
by increasing the intersolubility of reagents Kith the aid of cosolvents and by
selecting favorable reaction conditions. Dioxane (24 , 128), tertiary aromatic
bases (108, log), and tertiary butyl alcohol (140) are some of the proposed
solvents. High yields of monoglycerides are claimed when soaps of iron, nickel,chromium, or manganese (148) are used as catalysts, although the reasons forsuch behavior are not clear. These and similar procedures produce monoglycerides
of 80-90 per cent purity. Heating for 2 hr. at 14O-16O0C. with a large excess of
glycerol has been found to favor the formation of monoglycerides of fa tty acids
from castor oil (141a). Liquid-liquid extraction of monoglycerides by solvent
mixtures such as ethanol-hexane ( 5 3 ) or ethanol-heptane (G3) , fractional crys-
tallization from mixed solvents ( 5 3 ) , and single-solvent extraction (114) have
been applied to technical monoglycerides. Further, molecular distillation (92,
141, 149) was reported to yield products with about 90 per cent monoester con-
tent.Eckey’s “directed intereFterification” (303, 48), according to which natural
fats can be segregated into saturated and unsaturated triglycerides, has been
modified to produce monoglycerides and diglycerides of high purity (49). Accord-ing to this procedure mixtures of triglycerides and glycerol are subjected in the
presence of a highly active catalyst (sodium methoxide) to an interesterification
process combined with simultaneous fractional crystallization. There is a strongtendency for mono- and diglycerides to precipitate in preference to triglycerides ;
depending on the amount of added glycerol the precipitated glyceride is either
practically pure monoglyceride or diglyceride. Interesterification of cottonseed
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S YNT HE S I S O F GLYCERIDES OF FATTY ACIDS 849
oil with 10 per cent of glycerol led, for instance, to the precipitation of an almost
pure a-monopalmitin. The method has been used with good results for the prepa-
ration of various a-monoglycerides (81). Direct esterification of fa tty acids withan excess of glycerol (ten times the theoretical quantity) in a homogeneous
medium had been known to produce essentially a-monoglycerides. The reactionbetween chlorides of fa tt y acids and an excess of glycerol in a homogeneous
medium has been recently made possible by the use of N,N-dimethylformamide
as cosolvent (70). The formation of diglycerides in the course of this reactionwas inhibited by complexing glycerol with compounds such as potassium thio-
cyanate (72). This and similar syntheses are based on the differing reactivities
of the primary and secondary hydroxyl groups of glycerol with fa tty acids,
differences which have been recently reinvestigated and confirmed (1 15, 116,
117).Whereas the purity of saturated a-monoglycerides obtained by earlier investi-
gators remained on the whole unsurpassed, the preparation of pure unsaturatedmonoglycerides was made possible only recently, owing to improved methods
of preparing pure unsaturated fa tty acids. a-Nonoolein, a-monoelaidin, a-mono-linolein, and a-monolinolenin (32, 34, 38) have been prepared in high degree of
purity and in good yields by the action of the corresponding fa tty acid chlorideson acetoneglycerol, a-3lonoerucin and a-monobrassidin (25) and a-monoglycerides
of chaulmoogric acid [13-(2-cyclopenten-l-y1) ridecanoic acid] and hydnocarpic
acid [1l-(2-cyclopenten-l-yl)undecanoiccid] (133) have been synthesized in a
similar way (67). A fairly pure a-monoolein has been obtained by the interesterifi-
cation of methyl oleate with glycerol in the presence of an alkaline catalyst,
followed by molecular distillation and crystallization from acetone (66).
Follon-ing an earlier communication (19) a general method for the preparationof unsaturated mono-, di-, and triglycerides has been suggested by Black and
Overley (20), according to which unsaturated acids are first halogenated (pref-
erably brominated), converted to acyl chlorides, ecterified by conventional
methods, and dehalogenated with zinc. Although it is claimed that this pro-
cedure overcomes the danger of configurational changes in unsaturated fattyacids, apparently litt le use has been made of it in synthetic work.
The thermal data and yields of unsaturated monoglycerides are shown in
table 1. It will be noticed that the melting points of both forms I and IT' are
higher for monolinolenin than for monolinolein, a result which is unexpected. hd -
mittedly the linoleic and linolenic acids used in this synthesis (34) were preparedby the debromination of tetrabromo- and hexabromostearic acids, respectively,
but a recent investigation ( I ) has shown th at such acids are practically freefrom trans isomers and therefore identical, a t least in this respect, with tho-e oc-
curring in nature.
The thermal data o n three hydroxy acid nionoglycerides prepared by an un-disclosed method 184), of a-monoarachidin (134) apparently prepared for thefirst time, and of a-monobehenin (13) are also shon-n in table 1.
The work on the synthesis of optically actiye monoglycerides reviewed someyears ago in this Journal (61) has been continued and a series of L-a-mono-
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850
, 0"
C .
32.0
56.0
47.0
68.5--
47.0
57.5
81.5
L. HARTMAN
TABLE 1
S o me r ecen t ly s yn t h es iz ed a -mo n o g l ycer i d es
Melting and Transition PointsAcid Radical
1 Form1 1 Form I1
Oleic. . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . .. . . . . .
Brassidic. . . . . . . . . . . . . . . . . . . . . . . . . . .Linoleic . . . . . . . . . . . . . . . . . . . . . . . . . .Linolenic. . . . . . . . . . . . . . . . . . . . . . . . . . .Hydnocarpic. . . . . . . . . . . . . . . . . . . . . . .
Arachidic . . . . . . . . . . . . . . . . . . . . . . .12-Hydroxystearic.. . . . . . . . . . . . . . .9, IO-Dihydroxystearic.. . . . . . . . . . . . .9,10,12-Trihydroxystearic.. . . . . . . .Behenic. . . . . . . . . . . . . . . . . . . . . . . . . . . .
"C.
35.0
58.5
50.0
71.0
12.3
15.7
49.0
58.5-59.0
83.5
67; 88
124.0
91; 125
87.2
Form I11
"C.
25.0
42.0
36.0
62.0--
39.5
53.5
77.0
F o r m IV
"C.
12.5
29.5
15.0
37.0
-22.8
-13.5
TABLE 2
Character i s t i cs o j L-a-monoglycer ides
Acid Radical
Acetic.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Propionic. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Butyric., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Caproic. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Enanthic
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Caprylic. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Pelargonic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Palmitic. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Stearic. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Melting Point
'C.
7-9
14-15
28-30
34-35
44
49-50
54-55
62-64
71-72
7 5 7 7
14.07
13.32
13.44
13.73
12.85
14.63
14.8914.38
14.61
13.78
14.04
13.43
13.89
14.52
12.89
Yield
9er cent
47.5
63.4
72.2
65.6
69.4
67.0
Yield
pe r cent
94.0
95.0
43.0
61.5
62.3
47.5
49.057.0
47.0
80.6
57.0
85.0
73.0
56.0
82.5
Reference
Reference
glycerides containing CZ o CIS acids with the exception of CIS,C16,nd C17 mem-bers has been prepared ( 5 ) . As in previous investigations, the monoglycerides
were produced by the acylation of D ( +)-acetoneglycerol and acid hydrolysis
of the acetone compounds. The hydrolysis of t he lower members (up to C,) wascarried out with 10 per cent acetic acid a t 60°C., whereas the higher members
were hydrolyzed with concentrated hydrochloric acid a t temperatures ranging
from -4OOC. t o -15°C. The characteristics and yields of the products areshown in table 2.
B. &Monoglycerides
The importance of 0-monoglycerides is illustrated by the fact th at substantialamounts of unsaturated monoglycerides of this type are present in intestinal
contents (112), and th at commercial monoglycerides invariably contain the&isomer (23).
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SYNTHESIS OF GLYCERIDES O F FATTY ACIDS
Saturated :
Caproic . . . . . . . . . . . . .Caprylic. . . . . . . . . . . .Capric. . . . . . . . . . . . . .Lauric . . . . . . . . . . . .Myristic. . . . . . . . . . . .Palmitic. . . . . . . . . . . .Stearic.. . . . . . . . . . . .
851
OC. T. ~ per cent
[ Unsaturated:
-a to -10 I ( 3 7 ) ‘ Oleic 23.5 68. . . . . . . . . . .29.8 (37) Ela idic , . . . . . . 5 4 . 2
4 0 . 4 ( 5 7 ) Linoleic . . . . . . . . . 8 . 9 30
51.0 ( 5 7 )
61.2 ( 5 7 )
6 8 . 5 ( 5 7 )
7 4 . 5 ( 5 7 ) 1
TABLE 3
B-Monoplwerides
Acid Radical Melting Point 1 Reference Reference
The start ing material in the synthesis of satura ted p-monoglycerides is a a’-
ditritylglycerol or preferably a, ’-benzylideneglycerol, the preparation of
which has been described more recently by Verkade and van Roon (147). Afteracylation the blocking group is removed by hydrogenolysis. However, this laststep prevents the application of the method to the synthesis of unsaturated
P-monoglycerides, since regardless of the conditions of hydrogenation a fully
saturated glyceride is always obtained (33) whereas acid hydrolysis results in
the acyl shift from the p- to the a-position. This difficulty has been recently
overcome by Mart in (106) with the use of boric acid.
Boric acid displaces the labile benzylidene group from the benzylideneglycerol
ester with simultaneous esterification of the free hydroxyl groups at temperaturesnot exceeding 100°C., especially if triethyl borate is used as solvent. The borate
esters are readily hydrolyzed with water to yield P-monoglycerides. Saturated
p-monoglycerides can also be prepared by this method, and better yields areclaimed than those obtained with the conventional method. Table 3 shows the
constants of unsaturated P-monoglycerides and also data on several saturated
p-monoglycerides prepared by the hydrogenolysis of benzylidene compounds
(37,57), some of them for the first time.Isomerization of a- and P-monoglycerides with 56 per cent aqueous perchloric
acid in chloroform solution (107) has shown the existence of an equilibrium inthe composition range of 90-92 per cent of the a-isomer and 8-10 per cent of the
,&isomer. This has been confirmed in the case of commercial monoglycerides
(23), and i t is possible tha t p-monoglycerides are widespread and occur in con-
centrations higher than hitherto believed.
V. SYNTHESIS O F DIGLYCERIDES
A . a ’-Diglycerides
Developments in the synthesis of a ,a’-diglycerides comprise: ( I ) the prepara-tion of pure diglycerides with one and two unsaturated acid components by the
use of the trityl technique (42,43,44)and by direct acylation of a-monoglycerides(16, 25, 29, 42, 45, 66, 67); ( 2 ) the synthesis of saturated diglycerides with theaid of new blocking techniques (10, 123, 131); and ( 3 ) the preparation of simplediglycerides by modified “directed interesterification’’ (14, 15, 49) and by the
direct acylation of glycerol (27, 72, 129).
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852 L . HBRTBISN
TABLE 4
a,a‘-Diglycerides with one a n d two unsa tura t e d acid c om pone n t s.
1 Transition o r Melting PointGlyceride
ikzDiolein.. . . . . . . . . . 25 .0
Dielaidin. . . . . . . . . . 55 . 0
Dierucin . . . . . . . . . . .
Dibrassidin . . . . . . . .Dilinolein. . . . . . . . . . .
Dilinolenin . . . . . . . . . .
Dihydnocarpin . . . . . . . .Diohaulmoogrin.. . . .
Laurylolein . . . . . . . . . .
Myristylolein , , . , . .Palmitylolein . . . . . . . . .Stearylolein . . . . . .
Elaidvlolein
46 .5
68.5
-2 . 6
-12 .3
49 . 0
59.0
32 .0
41 .0
46 .0
54 .0
54.0
49 .0
2 8 . 8
Stearylelaidin. . . . . . . 65.5-65.9
Form I1
“C .
20 .0
53 .0
41.5
66 .5
47 .0
57 .0
Form I11
“C.
0 . 0
49 .0
41 .0
63 .5
42.0
52 . 0
Yield(Based on
Acid Chloride)
per cenl
Approximately 70
Approximately 70
Approximately 70
50
57
Proof of Structure
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Refer-ence
The trityl technique and the direct acylation of a-monoglycerides may be
used for the preparation of both simple and diacid diglycerides, whereas themodified “directed interesterification” and direct acylation of glycerol produce
simple diglycerides only. TWO odifications of the trityl technique are employed,
depending on the type of diglycerides required. For the preparation of simple
diglycerides the starting material is the a-monotrityl ether of glycerol, which is
acylated with two moles of an acid chloride, whereupon the trityl group is re-moyed. Diacid diglycerides are prepared by the tritylation of a-monoglycerides,
introduction of a second acyl group, and removal of the blocking group. Another
proven method of synthesizing diglycerides based on the acylation of glycerol
a-iodohydrin (59) has not been lately in use, omjng to the unavailability of
iodohydrin.
The trityl method involves an acyl shift from the p- to the a’-position, which
does not occur in direct acylation procedures and in most of the new blocking
techniques to be described.
Table 4 hows the thermal data and other characteristics of diglycerides with
one and two unsaturated acid components obtained by the “trityl” method orby the direct acylation of a-monoglgcerides. It ill be noted that the melting
point of a-stearyl-a’-olein prepared by the direct acylation (29) of a-monostearin
is 5°C. lower than those of two other preparations (41, 45), one of which was
obtained by the same method. This emphasizes the difficulty of determining
accurately the thermal properties of some synthetic glycerides. Three other
instances of this kind are shown in tables 6 and 9.
Sew blocking techniques suggested recently for the synthesis of a ,a‘-di-
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S Y S T H E S I S OF G L Y C E R I D E S OF FATTY A C I D S 853
glycerides are interesting more on theoretical grounds than as preparative pro-
cedures, since they require more steps than conventional methods.One of them (131) is based on a successive building up of alcoholic groups of
glycerol according t o the following reactions (R = an alkyl group) :
RCOOCHzCOCl A RCOOCH,COCHS, --+
C H Tu' H+
(1) HzS04
( 2 ) K z C O z R C O O KRCOOCHzCOCH2OH (3 ) HBr + RCOOCHzCOCHzBr-
RCOOCHzCCOHzOCOR 5 RCOOCHzCHOHCHzOCORS i
By labelling the glycerol carbon atoms during the synthesis and using a radio-
active fa tty acid a detailed structural knodedge of the glyceride could be ob-
tained.A modified procedure of synthesizing simple a , '-diglycerides from dihy-
droxyacetone (10) includes the protection of the ketone group as mercaptal to
avoid dimerization, acylation with propionic anhydride, and interesterificationof the a, '-dipropionoxyacetone diethylmercaptal thus obtained with methyl
esters of long-chain fat ty acids. The mercaptan is removed with mercuric chlo-
ride, and the ketone group is reduced in the presence of Raney nickel.
Another example of preparing simple a , '-diglycerides without an acyl shiftis provided by the following procedure (123), which uses a , '-benzylidene-
glycerol as starting material. The remaining free hydroxyl group of this com-pound is protected with a benzyl group, the benzylidene block is removed by
acid hydrolysis, and the P-benzylglycerol is acetylated. The long-chain fatty
acids are introduced by interesterificatioii in the presence of sodium methoside
(85 per cent yields), whereupon hydrogenolysis produces the a ,a'-diglycerides
(yield 97-98 per cent). The melting points of dipalmitin (73.5"C.) and distearin
(SOOC.) obtained by this method were slightly higher than those reported for
preparations by the trityl method ( 7 2 5 ° C . and 79.5"C., respectively) (79).
The use of allyl alcohol as starting material has also been suggested (10).
An ether is formed with 2,3-dihydropyran, followed by oxidation with potas-
sium permanganate to a-tetrahydropyranylglycerol, cylation of the p ,a'-hy-droxyl groups, and removal of the blocking group by acid hydrolysis. There
appears to be no advantage over the trityl method.
Glycidyl esters have been reported (76, 85) to react smoothly with fatty
acids at about 130°C. with the formation of a , '-diglycerides. a-Laury1-a'-
stearin (m.p. 62-64"C., yield 25 per cent) and a-erucyl-a'-stearin (m.p. 56-5i°C.,
yield 40 per cent) have been prepared by this method. In conjunction with
the preparation of glycidyl esters from epichlorohydrin and sodium soaps
(86,8i ), this would provide a general method for the preparation of both a-mono-
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854 L. HARTMAN
Dilaurin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Dimyristin.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Dipalmitin.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Dimargtrrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Distearin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
T A B L E 5
a , ' -Diglycer ides prepared by modified directed interesterif ication
"C .57 . 8
66.8
7 4 . 2
TG.3
79 . 4
Glyceride
! Crystallization
j Point Reference
emperature
i i i Initial 1 Final Iper cent
72
81
86
86
80
87
70
glycerides (by the acid hydrolysis of glycidyl esters) and a , '-diglycerides,
but the procedure is time-consuming and not devoid of difficulties.As mentioned in the section on a-monoglycerides, the modified "directed
interesterification" of fats results in the formation of diglycerides if the reac-
tion is carried out in the presence of suitable proportions of glycerol (14, 49).
Natural fats containing principally one kind of saturated acid may be used,but better yields and purer products are obtained if mixtures of simple triglyc-
erides and triacetin are interesterified and progressively crystallized (15).
The initial and final temperatures of crystallization and the melting points
of diglycerides thus obtained are shown in table 5 . With the exception of di-
elaidin and distearin the melting points are the highest ever reported.Direct esterification of glycerol with chlorides of fa tty acids has also been
used to prepare a , '-diglycerides, Dipalmitin (m.p. 73.0-73.5"C., yield 64
per cent) was obtained by reacting a mixture of glycerol and quinoline with a
solution of palmityl chloride in chloroform a t 10-15°C. (129). More recently
(27) dilaurin (m.p. 56.5"C.), dipalmitiii (73.5"C.), and distearin (78.7"C.)
mere obtained by the same method. By carrying out the reaction at room tem-
perature in a solution obtained by the addition of S ,N-dimethylformamide(72), dipalmitin (map.73.5-74"C., yield 67 per cent) and distearin (m.p. 80"C.,yield 72 per cent) were prepared. The high melting points of the final products
indicate that there is no appreciable formation of triglycerides under these
conditions.
B. a ,@-Diglycerides
The preparation of a ,@-diglycerides by the hydrogenolysis of a , -diacyl-a'-tritylglycerol (146) has been extended to diglycerides with two componentacids (145), such as a-palmityl-@-stearin and a-stearyl-S-palmitin. However,
the best method for the preparation of a,p-diglycerides, especially with onecomponent acid, seems to be that employed by Home and Malkin (74), whichis a modification of the procedure of Sowden and Fischer for the synthesis ofoptically active a ,@-diglycerides(139). It is illustrated by the following reac-tions:
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SYNTHESIS O F G L Y C E R I D E S OF FATTY A C I D S 855
Dilaurin. . . . . . . . . . . . . . . . . .Dirnyristin., . . . . . . . . . . . . . .
Dipalmitin... . . . . . . . . . . . . .Distearin.. . . . . . . . . . . . . . . .a-Stearyl-@-palmitin.. . . . .
CH, OH CH2OCHzCsHg
Fo r m I
".39.0
54 . 0
5 9 . 0
63 .5
71.0
68.5-69.5
I 10% aq. ~
CH3 CH3COOHH-0
a, C6HsCHa
C
CH3 CsHSCHzC1 'H-0
C
CH,i / \CH2-0
CH2 0CH2 Cs Hg
ICH3
/ \CH2-0
CHzOCHzCsHh CH2 OH
HZ Pd) 'CsHsN 1 Cs&c I HOCOR
2RCOCI ICHOH - HOCORICH2 OH CHZOCOR CH2OCOR
The method can be adapted to the preparation of cu,p-diacid diglycerides by
carrying out a two-stage direct acylation of a-benxylglycerol.The melting points of various preparations of CY,@-diglyceridesre shown in
table 6.
Sowden and Fischer's original method (139) was used by its authors for the
preparation of optically active C Y , P-dibutyrin, CY ,P-dipalmitin, and C Y , p-di-
stearin from D(+)-acetoneglycerol. Owing to the need fo r distilling D(+)-cY ,p-dibutyrin, a process which could induce some racemization, this compound
TABLE 6
LY ,@-Diglycer idesI hIelting Point I yield(Based on
AcidChloride)
Glyceride
a-Palmityl-@-stearin.. . . . . I 60.5-61.0
Form I1
".20.0
37.5
5 0 . 0
59 .5
per cefll
62.4
66 .4
81.8
70.6
83 .7
83.7
Proof of Structure
Conversion t o @-palrnityldi.
Conversion to a-palmityl-@-
stearin
stearyl-a'-tritylglycerol
TABLE 7Op t i ca l l y a ct ive a , @ -d i g l p er i d e s
Reference
Glyceride
D-a,@-Dibutyrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58-59
L-a,@-Dimyristin . . . . . . . . . . . . .. . . . . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . 58-59
wa,@-Dipalniitin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67-67.5
68-60
D-a,@-Dimyristin
D-a,@-Distearin,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i4 .5 -75
76-77
~
per cent
60.2
35 .5
58 .5
64 .1
52 .5
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856 L. H A R T M A N
might not have been optically pure. By an essentially similar method D-c ~ , @ -
dimyristin (6) and L-a P-dimyristin (7) have been prepared. The character-istics of all these products are shown in table 7.
The above-mentioned methods involve hydrogenolysis and therefore cannotbe used fo r the synthesis of unsaturated a ,0-diglycerides. It appears, however,th at the preparation of D- and ~-a,j?-diolein as now been accomplished (3);
this represents a major advance in glyceride synthesis.
VI . S YKT HE S I S OF TRIGLYCERIDES
A . Simple triglycerides
Whereas saturated triglycerides, both simple and mixed, had been preparedin a high degree of purity by earlier investigators, the synthesis of pure triglyc-
erides containing one or more unsaturated acids was delayed until these acids
became available in a sufficiently pure state. Certain procedural difficultiesdue to the instability of unsaturated acids had also t o be overcome. Although
such a comparatively simple triglyceride as triolein has been prepared by a
variety of methods during the last hundred years, its first really Satisfactory
preparation (as well as that of trilinolein) was accomplished in 1940 (151).
The method consisted in esterifying glycerol directly with pure oleic acid in
an inert atmosphere with p-toluenesulfonic acid as catalyst. (Incidentally, the
esteraselike action of various alkylarylsulfonic acids was the subject of a recent
comprehensive study (la) )
Triglycerides of other unsaturated acids were obtained later by the acylation
of glycerol with the corresponding fatty acid chlorides (34, 113) and by the
esterification of a-monoglycerides with fatty acids in uucuo at 100°C. in the
presence of acid catalysts (25) or ivith fatty acid chlorides in the presence ofpyridine (25, 67). Their characteristics are shown in table 8.
Triglycerides in about 70 per cent yield may also be prepared by the inter-
esterification of methyl or ethyl esters of fatty acids with glycerol in the presenceof alkaline catalysts (64, 83). The interchange between the above esters and
triacetin in the presence of sodium alkoxide (64, 88) provides another means
TABLE 8
Simple r ig lycer ides of unsatura ted acids
GlycerideTransition Point
~ Reference
Form I 1 Form I1 1 Form I11 1 Form IV I
Triolein. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Trielaidin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Tripetroselaidin . . . . . . . . . . . . . . . . . . . . . . .Trierucin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Tribrassidin . . . . . . . . . . . . . . . . . . . . . . . . . . .Trilinolein . . . . . . . . . . . . . . . . . . . . . . . . . .
Trilinolenin . . . . . . . . . . . . . . . . . . . . . . .Triiiydnocarpin . . . . . . . . . . . . . . . . . . .Trichaulmoogrin . . . . . . . . . . . . . . . . . . . . .
"C
5 . 5
4 2 . 0
5 2 . 5
30.0
59.0
-12.9
- 24 .2
34.0
44.5
".-13.0--
25.0-
-
31 . 0
41.5
"C .
-32.0
37.0
18.8
17.0
50.0
- 45 .6
- 44 .6
24 .0
35.0
"C .
15.5
6.0
43.0
-
-
--
15 .0
27.0
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S YXT HE S I S O F GLYCERIDES OF F A T T Y ACIDS 857
of obtaining triglycerides, and pure trieleostearin, unobtainable by the direct
esterification of eleostearic acid owing to gelation, has been prepared by thismethod (88). Since methyl esters are purified more easily than fatty acids, the
above-mentioned methods seem to offer certain advantages from the stand-point of cost and simplicity, especially in the preparation of large samples.
B. Diacid triglycerides
Here again it was the preparation of triglycerides with one or more unsaturated
acid components which presented problems. In particular, difficulty is experi-
enced in the introduction of the third acyl group into the molecule, whether
this acyl group be saturated or unsaturated. At room temperature the reac-
tion with acid chlorides does not proceed beyond the diglyceride stage, as has
been noticed by earlier investigators ( 2 ) and repeatedly confirmed later. Only
to obtain satisfactory yields (40).It has been suggested (104) tha t even under these conditions a certain amount
of diglyceride escapes acylation, and that the only method of obtaining a pure
final product is to use an extravagant excess of acid chloride (about four times
the theoretical quantity) a t about 80°C. Although this procedure has proved
successful, the use of such an excess of compounds as reactive as acid chlorides
a t elevated temperatures presents the danger of side reactions. A moderate
excess of acid chloride (5-10 per cent) and the removal of residual diglyceridesby chromatography on alumina (29) appears more satisfactory.
It seems that the difficulty is connected primarily with the cis-configuration,because Bomer and Knpeller succeeded in preparing a-palmityldielaidin and
a-stearyldielaidin at room temperature (21). I t may be a case of steric hin-
drance, which would be less pronounced with trans acids.
Triglycerides containing an unsaturated acid in the a-position have been
prepared by refluxing a chloroform solution of an unsaturated a-monoglyceride
with t\To moles of a saturated acid chloride in the presence of quinoline or
pyridine. The unsaturated a-monoglycerides were monoolein (38, 96), mono-
linolein ( 3 5 ) , and monoelaidin ( 3 2 ) . Conversely, a-saturated-p, a'-unsaturated
glycerides were prepared from saturated a-monoglycerides and chlorides of
unsaturated fa tt y acids in chloroform-pyridine solution under reflux condi-
tions ( 3 2 , 35 , 4 5 , 113).
Symmetrical diacid triglycerides with an unsaturated or a saturated acidin the @-position were obtained by the reaction of a,&-diglycerides with ap-
propriate (unsaturated or saturated) acid chlorides (79, 100, 104, 113).
All these types of triglycerides are listed in table 9. Certain anomalies re-
garding molecular weight determinations, refractive indices, and melting points
of some of the series have been discussed by Daubert and Longenecker (41).The melting points of two preparations of a-palmityldielaidin differ by 6°C.
It was pointed out that the lower melting point was not due to a metastablepolymorph (113).
Special thermal and diffraction characteristics are exhibited by diacid tri-
by maintaining the reaction mixtures at 50-80°C. for several hours is it possible *
'$%
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858 L. HARTMAN
TABLE 9
Diac id t r ig lycer ides c onta i n ing one or two unsatura ted acid components
Glyceride
a-Oleyldicaprin
a-Oleyldihurin , . . . . . . . . . . .
a-Oleyldimyristin
a-Oleyldipalmitin. . . . . . . . . . . ,
a-Oleyldistearin
a-Elaidyldicaprylin . . . . . . . . . .a-Elaidyldicaprin. . . . . . . . . .or-Elaidyldilaurin . . . . , . . . . , . .a-Elaidyldimyristin. . . . . . . . .
a-Linoleyldicaprylin . .. . . . . .
or-Linoleyldicaprin . . . . . . . . .a-Linoleyldilaurin. . . . . . . . .a-Linoleyldi myristin
or-Linoleyldipalmitin. . . . . . . , . .a-Linoleyldistenrin... . .a-Caproyldiolein . . . . .a-Caprylyldiolein.. . .or-Capryldiolein . . .
. . . . ... .
a-M yristyldiolein . . . . . . . .. . . . .or-Palmityldiolein . . . . . . . . . ,
a-Stearyldiolein.. . . . . . . . . . .or-Lauryldilinolein.. . . . . , . . . . .or-Myristyldilinolein . . , . . . .a-Palmityldilinolein. . . . . . . . . .a-Stsaryldilinolein. . . . . . . . . .
a-Capryldielaidin . . . . . . . . . .a-Lauryldielaidin.. . . . .. . . .a-Myristyldielaidin. . . . . . . . . .a-Palmityldielaidin. . . . . . , . . .
a-Palmityldipetroaelaidin.. . .a-Stearyldipetroselaidin , . , , . .8-Oleyldicaprin.
, ... .
... .
. .@-Oleyldilaurin. . .. . . . . . . . . .
pOleyldimyristin. . . . . . . . . .,9-Oleyldipalmitin.. . . . . . . . . .@-Oleyldistearin... . . . . . . . . . . .@-Elaidyldipalmitin. . . . . . .8-Elaidyldistesrin . . . . . . . . . . .8-Petroselaidyldipalmitin... .,9 .Petroselaidyldistearin.. . . . . .
8-Palmityldielaidin. . . . . . . . . . .&Stasryldielaidin. . . . . . . . . . .
Form I
"C
5.3
15.5
25.0
34.5
38.5
43.5
3. 0
15.0
27.0
39.5
.13 to --I
-1 to 0
15-16
20-21
26-27
32-33
-14.5
-18.5
-0.6
4. 3
13.3
15.8
22.9
.12 to - 1-9 to --I
-4 to -:5-6
25.0
35.5
40.0
46.0
40.3
40.4
55.0
5-614.5-15
28.5
37.5
43.5
55.0
61.0
54.9
02.6
44.5
50.1
Melting Point
orm !
"C .-2.5
4.8
22.7
-
-
42.5
33.0
35.9
20.5
35.0
41.5
52.5
58.0
54.3
32.0
43.2_.
Form I11
"C .-15.0
-10.0
18.6
29.8
-
-
-34.2
16.5
-10.9
-4.2
2.5
8.6
19.0
29.0
37.0--
Form I7
"C.
-27.0
__
-15.5
3. 8
18.5
26.7
30.4
-50.5
-50.0
-40.5
-32.0
-21.8
-13.2
-1.5
22.8
26.4
31.5
11.0
21.5
29.5
42.0
46.0
35.9
43.4
26.0
34.0
Form V
"C.
2.0
12.0
23.0
33.0
40.0
___
Proof of Structure
Hydrogenation to
a-stearyldi-
aoylins
a-stearyldi-
aoylins
a-stearyldi-
acylins
a-stearyldi-
acylins
a-stearyldi-
acylins
Hydrogenation to
Hydrogenation to
Hydrogenation to
Hydrogenation to
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogen at on
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Hydrogenation
Refer-
ences
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SYNTHESIS OF GLYCERIDES O F FATTY ACIDS
8-Butyryldistearin . . . . . . . . . . . . .8-Caproyldipalmitin.. . . . . . . . . .8-Caproyldistearin. . . . . . . . . . . .8-Palmityldiacetin., . . . . . . . . . . .8-Stearyldiacetin . . . . . . . . . . . . . .u,@-Diacetylolein.. . . . . . . . . . . .u,,%Dibutyrylolein.. . . . . . . . . .8-Behenyldipalmitin. . . . . . . . . . .,3-Behenyldistearin.. . . . . . . . . . . .a-Palmityldibehenin . . . . . . . . . .a-Stearyldibehenin. . . . . . . . . . . .
859
“C.
54 . 8
44.5
53.1
37 . 0
43.5
-17.5
-29.0
47.4
56.0
51i.9
61.3
TABLE 10
Diacid t r iglycer ides containing CI-CB or CZZa t t y a ci d s
Glyceride
a,B-Diacetylpalmitin. . . . . . . . . . . .a.@-Diacetylstearin.. . . . . . . . . . . .a,p-Diacetylbehenin. . . . . . . . . . . .u @-Dipropionyktearin . . . . . . . .u,,3-Dibutyrylpalmitin. . . . . . . . .u,@-Dibutyrylstearin.,. . . . . . . . .a,B-Dicaproylpalmitin,. . . . . . . . .a&Dicaproylstearin., . . . . . . . . . .B-Acetyldipalmitin. . . . . . . . . . . . . .,3-.lcetyldietearin. . . . . . . . . . . . . . .@-Butyryldipalmitin, . . . . . . . . . . .
MeltingPoint
“C .
22 . 4
34.1
53.1
23.5
2.9
15.6
-7 . 4
6. 0
54 . 8
62.8
46.5
MeltingPoint
lyceride
II
eference Reference
glycerides containing very short (C2 to C,) or unusually long ((322) fat ty acidchains. A number of such glycerides have been prepared by conventional methods
(acylation of a-monoglycerides and a , ‘-diglycerides, respectively), some of
them for the first time (66, 78, 80, 81, 82). These glycerides are listed in table
10. Because of the great variety of modifications the highest melting pointsonly are shown, and the original papers should be consulted for details.
Monoacyldiacetins have been also obtained by the interesterification of
natural fa ts and triacetin in the presence of sodium methoxide, followed by
fractional distillation and hydrogenation (12, 13). Several acetostearins and
acetooleins with different degrees of acetylation have been recently preparedfrom the corresponding a-monoglycerides and acetic anhydride (54, 55 , 56).
It seems that all these products have a future as plasticizers and coatings inthe food and other industries (12 ,65 ,78 ,93).
C . Triacid triglycerides
I n principle any triacid triglyceride of saturated long-chain acids is obtainable
by the trityl method according to the following scheme (R = an alkyl group) :
CH2OCOR CH2OCOR
ICHOH
HCl__f
CH20COR CH20 COR
I R”COC1 ICHOH - HOCOR”I
CH2OCOR’ICH2 OCOR’
By varying the kind of a-monoglyceride and the sequence of acylation thethree possible isomers of a given triglyceride may be prepared. Using a-mono-stearin as starting material Chen and Daubert (30) prepared by this methodfour groups of isomeric glycerides containing C l 0 o C18 acids. Some of these
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860
Glyceride
llIyristyllaurylcaprin. . . . . . . . . . . . . . . . . . . . . . . . . .Palmitylmyristyllaurin.. . . . . . . . . . . . . . . . . . . . .Stearyllaurylcaprin . . . . . . . . . . . . . . . . . . . . . .Stearylmyristylcaprin . . . . . . . . . . . . . . . . . . . .Stearylpalmitylcaprin. . . . . . . . . . . . . . . . . . . . .
Stearylmyristyllaurin . . . . . . . . . . . . . . . . . . . . . . .Stearylpnlmityllaurin... . . . . . . . . . . . . . . . . . . . . . . .Stearylcaprylmyristin.. . . . . . . . . . . . . . . . .Stearyllaurylmyristin . . . . . . . . . . . . . . . . . . . .Stearylpalmitylmyristin. . . . . . . . . . . . . . . . . . . . . . .Stearyloaprylpalmitin . . . . . . . . . . . . . . . . . .Stearyllaurylpalmitin . . . . . . . . . . . . . . . . . . . . . . . . . . .
Stearylmyristylpalmitin., . . . . . . . . . . . . . . . . . . . . . .
Stearylcayryllaurin . . . . . . . . . . . . . . . . . . .I
L. H A R T M A N
Transition Point
Form I Form I1 Form 111
". 'C. "C .36.5-37.0 33-34 22.0
48.5-19.0 44.0 36-37
44.0 40.0 14.5
45.0 42.0 21.5
50.0 46.5 26.1
41.8 - 22.3
49.5 45.5 27.5
52.0 , 47.0 33.4
52.5 50.1 14.0
55.0 25.8
55.0 53.8 20.1
57.5 56.0 32.0
5 $ . 5 ii:: ~ 40.3
59.5 56.1 1 40.6
TABLE 11
Satura ted t r iacid t r ig lycer ides
glycerides displayed an unusual behavior, inasmuch as they did not crystallize
from solvents in their highest-melting modification without being equilibrated
at 25°C. for 12 hr. or more. Their characteristics and those of two other glyc-erides prepared by Sidhu and Daubert (136) are shown in table 11.
If one of the component acids is of lorn molecular weight or unsaturated,
and therefore has a low melting point, complications arise, since a P-diacyl-a'-
trityl intermediates containing such ail acid are difficult to obtain in a pure
state and in good yields. Incidentally this difficulty was evident in the synthesis
of unsaturated a , '-diglycerides by the trity l method (42).To avoid this difficulty, Verkade (143) used c y , P-diglycerides of high-meltingacids as intermediates in the preparation of the two isomeric triglycerides
containing a low-melting acid in the a'-position. The third isomer with the
low-melting acid in the 0-position was obtained from a , '-diglycerides of high-
melting acids. Thus in each case the low-melting component was introduced
in the final step. Proceeding in this way, three isomeric butyrylpalmitylstearins
and oleylpalmitylstearins were prepared. The isomeric oleylpalmitylstearins
have also been prepared recently from a ,a'-diglycerides obtained by directacylation (29, 7 2 ) , a procedure which is much simpler, although perhaps less
satisfactory from the theoretical point of view.
The characteristics of the products, including thermal data determined onsome of them by Lutton (96), appear in table 12.
The earlier observation (4) that enantiomorphic triglycerides containingonly aliphatic acid residues do not possess a detectable optical rotation hasbeen confirmed (137, 139), although n o extensive work has been carried outon this subject. It is characteristic that even the acetylation of D(+)-a,P-di-
stearin (139) led to the disappearance of the optical activity, whereas the meth-anesulfonyl derivative (8) was optically active. There seems to be little doubt
th at the lack of measurable optical act ivity in most natural fats does not pre-
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S YKTHES IS OF GLYCERIDES OF FATTY d C I D S
Melting o r Transition Point YieldGlyceride ~ (Based o n
I Form I I Form I1 1 Form 111
861
Reference
39.5-40.5
36.5-37.5
37.3
29.5
Stearylpalmitylbutyrin . . . . . . . . . . . . . . . .
Palmitylstearylbutyrin . . . . . . . . . . . . . . . . . . . . . .Palmitylbutyrylstearin . . . . . . . . . . . . . . . . . . . .Stearylpalmitylolein . . . . . . . . . . . . . . . . . . . . . . . . . .
Palmitylstearylolein . . . . . . . . . . . . . . . . . . . . . . . . . . .
Palmityloleylstearin
Palmityloleyllaurin
40.2
39.8
33.0
"C
25.3
26.3
18.2
p e r cent
8 i
91
87
86
84
78
67
clude their being enantiomorphs. This might be to some extent responsiblefor the discrepancy in melting points between synthetic DL-triglycerides and
those isolated from natural sources.
VII . CRITERIA OF PURITY AXD STRUCTCRE
A . Oxidat io n wit h per iodates
Chemical methods do not provide on the whole a satisfactory measure ofpurity. As already mentioned, a-monoglycerides are the only glycerides that
can be estimated specifically with some degree of accuracy. The two original
procedures based on the oxidation of free hydroxyl groups of a-monoglycerides
with periodic acid (122) and with sodium periodate ( 7 7 ) have been followedby numerous modifications (47, 50, 69, 71, 89, 121) which make possible the
determination of these compounds within 1 per cent in the presence of other
glycerides and-in some procedures-of free glycerol. P-hlonoglycerides do
not react, but by combining periodate oxidation with isomerization with per-chloric acid (107), which produces an equilibrium between the two types of
monoglycerides, the approximate content of p-monoglycerides can be computed.
B. Chromatographic methods
Chromatography on silica gel was apparently used for the first time by Sidhuand Daubert (135) to determine the homogeneity of synthetic diacid diglycerides.
Recently several chromatographic methods have been suggested for the ideiitifi-cation and separation of various types of glycerides. -4 rocedure using glass-
fiber filter paper impregnated with silicic acid (46) resolves mixtures of a-mono-glycerides, a , '-diglycerides, and triglycerides with the aid of ethyl ether-
isooctane solvent systems and with sulfuric acid as reagent for the detection
of spots. Other chromatographic procedures applied to glyceride mixturesinclude: paper chromatography wing various indicators such as a-cyclodextrinand iodine, lend tetraacetate, and lipase (62, 105); oxidation with periodatefollowed by separation on silicic acid ( 2 2 ) diiplacement chromatography
with charcoal as the absorbent (68); elution chromatography OH siiica gel (127).
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862 L . HARTMAN
A survey of paper chromatographic procedures investigated in the Hormel
Inst itute a t the University of Minnesota (130) contains a number of suggestionsfor the qualitative and quantitative analysis of glycerides.
Molecular distillation of glycerides pe r se or in conjunction with chromato-
graphic analysis has also been recommended as a general criterion of puri ty(125) .
C . Thermal and x-ray investigation
Th e work on the thermal and x-ray patterns of glycerides, generally accepted
as important criteria of puri ty and structure (95), has been actively pursued
and a large amount of new da ta has been published. Unfortunately this progresshas been accompanied by considerable confusion, owing to the disagreement
between leading authorities regarding results and their interpretation (97,
101). In addition to the previously known three modifications of a-monoglyc-
erides, a fourth modification has been reported (99). 0-Monoglycerides havebeen examined for the first time (36 ,57) and found to exhibit no polymorphism.
Reexamination of simple a:,a’-diglycerides (14) has shown the existence of
two forms only and not of three, as previously reported (103). However, ac-
cording to Malkin (101) three forms do exist; three modifications have beenalso found for a, -diacid diglycerides (135). The investigation of the poly-
morphism of a ,P-diglycerides (74) disclosed two solid modifications. The poly-
morphism of the mono- and diglycerides of cis and trans monounsaturated
fatty acids (25) was found to be similar to tha t of the corresponding saturated
compounds, but the mono- and diglycerides of linoleic and linolenic acids (34,43) behaved differently.
The confusion noticeable in the opinions on the polymorphism of mono-and diglycerides is still more pronounced with regard to triglycerides. Whereas
Malkin distinguishes four modifications of triglycerides, which include a vitreous
form (101), Lutton (94) and other American investigators (9 , 58) have denied
the existence of the vitreous form but have reported several additional modi-
fications (80, 82). Until these differences are resolved, both the existence and
the nomenclature of various modifications remain uncertain.
D . Infra red spectra
The infrared spectroscopy which is finding increasing application to fatty
acid derivatives (119, 150) has produced some results of interest to the syn-thesis of glycerides. The extension of the determination of trans monounsaturated
acids by the infrared technique (132) to acids of higher unsaturation has re-
vealed, as mentioned previously, that linoleic and linolenic acids, obtainedby the debromination technique, contain only traces of trans isomers (1).This
should remove reservations against their use in synthetic work.Infrared spectra have been used for the identification of monoglycerides
in the presence of triglycerides (90, 91) by the “finger-print” technique; further,the spectra of mono-, di-, and triglycerides have been studied (120) with theview of developing analytical procedures. Both qualitative and quantitative
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S YNTHES IS OF GLYC ER IDES OF F ATTY AC IDS 863
determinations of mixtures of these compounds might be achieved by examining
characteristic bonds in the region of 3.0 and 9.0 microns.In a series of remarkable papers Chapman has described the infrared spectra
of cy - and P-monoglycerides (26) , cy , cy’-diglycerides and simple triglycerides (27),
and diacid triglycerides (28) in relation to their polymorphic transitions. Onthe whole his results support Lutton’s views rather than Malkin’s on the poly-
morphism of the glycerides in question.
E . Conclusive proof of structure
Whereas the structure of mono- and diglycerides can be verified by their
conversion into triglycerides, the only dependable proof of the position of
fatty acids in isomeric triglycerides is based on the reliability of methods used
in their preparation. Mixed triglycerides containing unsaturated acids haveusually been identified by hydrogenation and comparison with the corresponding
fully saturated compounds (79), but recent investigations of the major com-ponent glyceride of cocoa butter (29, 98, 129a) have convincingly demonstrated
the inadequacy of any single analytical method for determining the structure
of such glycerides. Only by employing several independent methods was it
possible to arrive at a definite conclusion on this point; moreover, the mostimportant requisite was the availability of synthetic compounds of known struc-
ture for comparative tests. Fortunately the present standard methods based
on the use of isopropylideneglycerol, benzylideneglycerol, and tritylglyceroloffer means of preparing a wide range of glycerides of known structure. These
preparations can serve as standards for comparison with products obtained
by less time-consuming, direct esterification methods. Hydrolysis of glycerideswith pancreatic lipase has been recently suggested as a means of determining
the position of fat ty acids in a glyceride molecule on the basis of the specific
action of the lipase on the primary hydroxyl group linkages of glycerol (110,
111). Although satisfactory results have been obtained with some glycerides,reports are conflicting and more work is required. In view of the comparatively
simple nature of glyceride molecules it is rather remarkable that , with the
exception of monoglycerides, for the time being there are no recognized analytical
procedures for the establishment of their structure. To some degree this ex-
emplifies the peculiar nature of f at chemistry.
VIII. R E F E R E N C E S
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864 L. HARTMAN
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